Recently, the Prospective Comparison of ARNI (angiotensin receptor–neprilysin inhibitor) with ARB (angiotensin receptor blocker) Global Outcomes in Heart Failure with Preserved Ejection Fraction (PARAGON‐HF) trial suggested that women might obtain more benefit than men from sacubitril/valsartan, compared with valsartan, in heart failure with preserved ejection fraction (HFpEF).1-3 However, the picture is more complicated as there was also an interaction between left ventricular ejection fraction (LVEF) and the effect of sacubitril/valsartan.2 Patients with a LVEF at or below the median (57%) seemed to gain more benefit from sacubitril/valsartan than those with a LVEF above the median.2 To make matters more complex still, it is well known that the distribution of LVEF is different in women and men, with women, on average, having a higher LVEF than men, be it in the general population or in individuals with heart failure (HF).4-6 Despite a higher LVEF, women with HFpEF had worse systolic function, as assessed by tissue Doppler echocardiography, compared to men with HFpEF.7 To further investigate the relationship between sex, LVEF and treatment in HF, we explored the effect of three different neurohumoral modulators in large trials which provide data on clinical outcomes in patients with HF, across the full range of LVEF, incorporating the three commonly described HF phenotypes – HF with reduced ejection fraction (HFrEF, LVEF <40%), HFpEF (LVEF >50%) and HF with mid‐range ejection fraction (HFmrEF, LVEF 40–50%).8

We pooled individual patient‐level data from: (i) three trials using an angiotensin receptor blocker – the Candesartan in Heart failure: Assessment of Reduction in Mortality and morbidity (CHARM) – the CHARM‐Alternative and CHARM‐Added trials in HFrEF and the CHARM‐Preserved trial in HFmrEF/HFpEF;9 (ii) three trials using a mineralocorticoid receptor antagonist (MRA) – two HFrEF trials, the Randomized Aldactone Evaluation Study (RALES) and the Eplerenone in Mild Patients Hospitalization and Survival Study in Heart Failure (EMPHASIS‐HF), and one HFmrEF/HFpEF trial – the Treatment of Preserved Cardiac Function Heart Failure with an Aldosterone Antagonist trial (TOPCAT).10-12 Only TOPCAT patients from the Americas were included; (iii) two trials using sacubitril/valsartan – the Prospective Comparison of ARNI with ACEI to Determine Impact on Global Mortality and Morbidity in HF trial (PARADIGM‐HF) in HFrEF and PARAGON‐HF in HFmrEF/HFpEF.1, 13

Cox proportional hazards modelling was used to analyse (i) the primary composite outcome (first occurrence of HF hospitalization or cardiovascular death); (ii) first HF hospitalization; and (iii) cardiovascular death. Likelihood ratio tests were used to report (i) two‐way interaction between treatment and sex; and (ii) three‐way interaction between treatment, sex and LVEF. LVEF, modelled as a fractional polynomial, and its interaction with treatment using the best fit model for each drug category (based on the primary composite outcome) was examined with the mfpi command in Stata. Models were stratified by trial for MRAs and sacubitril/valsartan. All analyses were conducted using Stata version 16 (Stata Corp., College Station, TX, USA).

This present analysis included 2400, 1938 and 4311 women and 5199, 4229 and 8884 men in the candesartan, MRA and sacubitril/valsartan trials, respectively (Table 1). Overall mean LVEF (%) was 38.9 ± 14.9%, 35.3 ± 16.0% and 39.7 ± 15.1%, respectively. Women had a higher mean LVEF, with the difference compared to men 6.3%, 9.4% and 10.3%, respectively. Women had a lower incidence of the primary composite outcome (and its components) in each of the treatment and control groups.

In keeping with prior reports from the CHARM Programme and TOPCAT, as well as a recent analysis of PARADIGM‐HF and PARAGON‐HF, we found that treatment with an ARB, MRA or ARNI may be of benefit beyond the upper limit of LVEF eligibility used in contemporary HFrEF clinical trials (40%) and may extend to what has been termed HFmrEF (LVEF 40–49%) and even to the lower part of the LVEF range currently categorized as HFpEF.2, 6, 14, 15 Importantly, the benefit of each treatment seemed to extend to a higher LVEF in women, compared to men (Figure 1). There was no difference in efficacy of therapy between men and women with HFrEF.

Because these are post hoc analyses, they are only hypothesis generating. However, the fact that all three neurohumoral modulating therapies demonstrated the same sex‐related pattern of response raises the possibility that the differential response between women and men identified in PARAGON‐HF may be real rather than due to the play of chance, although interpretation of PARAGON‐HF is more complex as it had an active comparator compared with a placebo control in the other trials. Despite this consistent observation in the trials examined, the biological basis for such a finding is uncertain. As detailed elsewhere, the possibilities include sex‐related differences in cardiac remodelling in response to blood pressure, age and other stimuli, and differences in age‐related arterial stiffening, which is more pronounced in women than men.3 Women may also have other evidence of contractile dysfunction, compared with men, for a given ejection fraction.3 Natriuretic peptide levels are lower in women with HFpEF than in men, and women may have reduced cyclic guanosine monophosphate‐protein kinase G signalling compared with men, especially after the menopause.3 The possibility that women with HF might benefit from treatment to a higher level of LVEF than previously considered could be of great clinical importance. Women with HF have fewer treatment options than men with HF because HFmrEF and HFpEF are the predominant HF phenotypes in women and no therapy has been approved by regulatory authorities for either of these phenotypes.6 More research on this matter is clearly required.

Conflict of interest: P.D. and A.J. report no conflicts. C.S.P.L., M.A.P., F.Z., B.P., S.D.S. and J.J.V.McM. or their institutions were paid for their participation in one or more of these trials. J.J.V.McM reports receiving fees (all fees listed paid to Glasgow University) for serving on a steering committee from AbbVie, Amgen, Bayer, Bristol‐Myers Squibb, Cardiorentis, DalCor Pharmaceuticals, GlaxoSmithKline, Novartis, Oxford University–Bayer; Vifor Pharma–Fresenius; fees for serving on an end‐point committee from Cardiorentis; fees for serving on an end‐point adjudication committee from Vifor Pharma–Fresenius; fees for serving as principal investigator of a trial from Theracos; fees for serving as co‐principal investigator of a trial from GlaxoSmithKline, Novartis; fees for serving on a data and safety monitoring committee from Merck, Pfizer; fees for serving on an executive committee from Novartis; advisory board fees from Novartis; and fees for travel support from AbbVie, Amgen, Cardiorentis, GlaxoSmithKline, Novartis, Oxford University–Bayer, Theracos, from Vifor Pharma–Fresenius. C.S.P.L. reports receiving grant support and fees for serving on an advisory board from Abbott Diagnostics, Amgen, Boehringer Ingelheim, Boston Scientific, Roche Diagnostics; grant support, fees for serving on an advisory board, and fees for serving on steering committees from Bayer; grant support from Medtronics; grant support and fees for serving on a steering committee from Vifor Pharma; fees for serving on an advisory board and fees for serving on steering committees from AstraZeneca and Novartis; consulting fees from Merck and Stealth BioTherapeutics, fees for serving on a steering committee from Janssen Research and Development; lecture fees and consulting fees from Menarini, and fees for serving on a scientific committee from Corvia Medical and holding a pending patent (PCT/SG2016/050217) on a method regarding diagnosis and prognosis of chronic heart failure M.A.P. reports receiving consulting fees from AstraZeneca, GlaxoSmithKline, Novo Nordisk, Sanofi, Jazz Pharmaceuticals, MyoKardia, Servier, Takeda Pharmaceutical, and Corvidia and consulting fees and stock options from DalCor Pharmaceuticals. F.Z. recieved personal fees for steering committee membership from Janssen, Bayer, Pfizer, Novartis, Boston Scientific, Resmed, Takeda, General Electric and Boehringer Ingelheim; consultancy fees from Amgen, CVRx, Quantum Genomics, Relypsa, ZS Pharma, AstraZeneca and GSK; he is the founder of Cardiovascular Clinical Trialists and CardioRenal. B.P. is a consultant for Bayer, AstraZeneca, Sanofi, Sarfez, scPharmaceuticals, Relypsa/Vifor, Stealth Peptides, Cytopherx (stock options). S.D.S. reports grant support and consulting fees (all fees listed paid to Brigham and Women's Hospital) from Alnylam Pharmaceuticals, Amgen, AstraZeneca, Bristol‐Myers Squibb, Gilead Sciences, GlaxoSmithKline, MyoKardia, Novartis, Theracos, Bayer, and Cytokinetics, grant support from Bellerophon Therapeutics, Celladon, Ionis Pharmaceuticals, Lonestar Heart, Mesoblast, Sanofi Pasteur, and Eidos Therapeutics; consulting fees from Akros Pharma, Corvia Medical, Ironwood Pharma, Merck, Roche, Takeda Pharmaceutical, Quantum Genomics, AOBiome, Cardiac Dimensions, Tenaya Therapeutics, and Daiichi Sankyo; fees for serving on a data and safety monitoring board from Janssen.

最近，ARNI（血管紧张素受体-脑啡肽酶抑制剂）与 ARB（血管紧张素受体阻滞剂）在保留射血分数的心力衰竭（PARAGON-HF）中的全球结局试验的前瞻性比较表明，女性可能比男性从沙库巴曲/缬沙坦中获得更多益处，与缬沙坦相比，在射血分数保留的心力衰竭（HFpEF）中。1-3然而，情况更为复杂，因为左心室射血分数 (LVEF) 与沙库巴曲/缬沙坦的作用之间也存在相互作用。2 LVEF 等于或低于中位数的患者 (57%) 似乎比 LVEF 高于中位数的患者从沙库巴曲/缬沙坦中获益更多。2更复杂的是，众所周知，LVEF 在女性和男性中的分布是不同的，平均而言，女性的 LVEF 高于男性，无论是在普通人群中还是在患有心力衰竭 (HF) 的个体中。 ）。4-6尽管 LVEF 较高，但通过组织多普勒超声心动图评估，与 HFpEF 男性相比，HFpEF 女性的收缩功能更差。7为了进一步研究性别、LVEF 和 HF 治疗之间的关系，我们在大型试验中探讨了三种不同的神经体液调节剂的作用，这些试验提供了 HF 患者在整个 LVEF 范围内的临床结果数据，包括三种常见的 HF表型——射血分数降低的 HF（HFrEF，LVEF <40%）、HFpEF（LVEF >50%）和射血分数中等的 HF（HFmrEF，LVEF 40-50%）。8

我们汇总了来自以下各项的个体患者水平数据：(i) 使用血管紧张素受体阻滞剂的三项试验——坎地沙坦治疗心力衰竭：降低死亡率和发病率的评估 (CHARM)——治疗 HFrEF 的 CHARM-Alternative 和 CHARM-Added 试验以及HFmrEF/HFpEF 中的 CHARM-Preserved 试验；9 (ii) 三项使用盐皮质激素受体拮抗剂 (MRA) 的试验 – 两项 HFrEF 试验、随机醛内酯评估研究 (RALES) 和依普利酮在轻度患者住院和心力衰竭中的生存研究 (EMPHASIS-HF)，以及一项 HFmrEF/ HFpEF 试验 – 使用醛固酮拮抗剂试验 (TOPCAT) 治疗保留的心脏功能心力衰竭。10-12仅包括来自美洲的 TOPCAT 患者；(iii) 两项使用 sacubitril/valsartan 的试验——ARNI 与 ACEI 的前瞻性比较，以确定 HFrEF 中 HF 试验 (PARADIGM-HF) 和 HFmrEF/HFpEF 中的 PARAGON-HF 对全球死亡率和发病率的影响。1、13

Cox 比例风险模型用于分析 (i) 主要复合结局（首次发生 HF 住院或心血管死亡）；(ii) 第一次心衰住院；(iii) 心血管死亡。似然比检验用于报告 (i) 治疗与性别之间的双向交互作用；(ii) 治疗、性别和 LVEF 之间的三向相互作用。LVEF，建模为分数多项式，并使用 Stata 中的 mfpi 命令检查使用每种药物类别的最佳拟合模型（基于主要复合结果）与治疗的相互作用。通过 MRA 和沙库巴曲/缬沙坦的试验对模型进行分层。所有分析均使用 Stata 版本 16（Stata Corp.，College Station，TX，USA）进行。

目前的分析包括坎地沙坦、MRA 和沙库巴曲/缬沙坦试验中的 2400、1938 和 4311 名女性和 5199、4229 和 8884 名男性（表1）。总体平均 LVEF (%) 分别为 38.9 ± 14.9%、35.3 ± 16.0% 和 39.7 ± 15.1%。女性的平均 LVEF 较高，与男性的差异分别为 6.3%、9.4% 和 10.3%。在每个治疗组和对照组中，女性的主要复合结局（及其组成部分）的发生率较低。

根据 CHARM 计划和 TOPCAT 之前的报告，以及最近对 PARADIGM-HF 和 PARAGON-HF 的分析，我们发现使用 ARB、MRA 或 ARNI 的治疗可能有益于超出使用的 LVEF 资格上限在当代 HFrEF 临床试验中（40%），并可能扩展到所谓的 HFmrEF（LVEF 40-49%），甚至扩展到目前归类为 HFpEF 的 LVEF 范围的较低部分。2, 6, 14, 15重要的是，与男性相比，每种治疗的益处似乎延伸到女性的 LVEF 更高（图1）。男性和女性 HFrEF 的治疗效果没有差异。

因为这些是事后的分析，它们只是产生假设。然而，所有三种神经体液调节疗法都表现出相同的性别相关反应模式这一事实提出了这样的可能性，即在 PARAGON-HF 中确定的女性和男性之间的差异反应可能是真实的，而不是由于机会的游戏，尽管解释与其他试验中的安慰剂对照相比，PARAGON-HF 更复杂，因为它有一个活性比较器。尽管在所检查的试验中观察到了一致的观察结果，但这种发现的生物学基础尚不确定。正如在别处详述的那样，可能性包括心脏重塑对血压、年龄和其他刺激的反应与性别相关的差异，以及与年龄相关的动脉硬化的差异，这在女性中比男性更明显。3对于给定的射血分数，与男性相比，女性还可能有其他收缩功能障碍的证据。3 HFpEF 女性的利钠肽水平低于男性，与男性相比，女性的环磷酸鸟苷-蛋白激酶 G 信号传导可能减少，尤其是在绝经后。3患有 HF 的女性可能会从治疗中受益于比之前认为的更高水平的 LVEF，这可能具有重要的临床意义。患有 HF 的女性比患有 HF 的男性有更少的治疗选择，因为 HFmrEF 和 HFpEF 是女性的主要 HF 表型，并且监管机构尚未批准针对这两种表型的治疗。6显然需要对这个问题进行更多研究。

利益冲突：PD 和 AJ 报告没有冲突。CSPL、MAP、FZ、BP、SDS 和 JJVMcM。或他们的机构因参与其中一项或多项试验而获得报酬。JJVMcM 报告从艾伯维（AbbVie）、安进（Amgen）、拜耳（Bayer）、百时美施贵宝（Bristol-Myers Squibb）、Cardiorentis、DalCor Pharmaceuticals、葛兰素史克（GlaxoSmithKline）、诺华（Novartis）、牛津大学拜耳（Oxford University-Bayer）的指导委员会工作收取费用（列出的所有费用已支付给格拉斯哥大学）；Vifor Pharma-费森尤斯；Cardiorentis 终点委员会的服务费用；在 Vifor Pharma–Fresenius 的终点裁决委员会任职的费用；担任 Theracos 试验首席研究员的费用；担任葛兰素史克、诺华公司试验的联合首席研究员的费用；在默克、辉瑞公司的数据和安全监测委员会任职的费用；在诺华执行委员会任职的费用；诺华的顾问委员会费用；艾伯维（AbbVie）、安进（Amgen）、Cardiorentis、葛兰素史克（GlaxoSmithKline）、诺华（Novartis）、牛津大学拜耳（Oxford University-Bayer）、Theracos 和 Vifor Pharma-Fresenius 的差旅支持费用。CSPL 报告从雅培诊断公司、安进公司、勃林格殷格翰公司、波士顿科学公司、罗氏诊断公司的顾问委员会中获得赠款支持和费用；拜耳的资助、顾问委员会服务费用和指导委员会服务费用；获得美敦力公司的支持；为在 Vifor Pharma 指导委员会任职提供支持和费用；在咨询委员会任职的费用以及在阿斯利康和诺华公司指导委员会任职的费用；默克和 Stealth BioTherapeutics 的咨询费，在杨森研发指导委员会任职的费用；来自美纳里尼的讲座费和咨询费，以及在 Corvia Medical 的科学委员会任职并持有关于慢性心力衰竭诊断和预后方法的未决专利 (PCT/SG2016/050217) 的费用 MAP 报告从阿斯利康收取咨询费， GlaxoSmithKline、Novo Nordisk、Sanofi、Jazz Pharmaceuticals、MyoKardia、Servier、Takeda Pharmaceutical 和 Corvidia 以及 DalCor Pharmaceuticals 的咨询费和股票期权。FZ 从杨森、拜耳、辉瑞、诺华、波士顿科学、瑞思迈、武田、通用电气和勃林格殷格翰收取指导委员会成员的个人费用；Amgen、CVRx、Quantum Genomics、Relypsa、ZS Pharma、AstraZeneca 和 GSK 的咨询费；他是心血管临床试验和心肾的创始人。BP 是拜耳、阿斯利康、赛诺菲、Sarfez、scPharmaceuticals、Relypsa/Vifor、Stealth Peptides、Cytopherx（股票期权）的顾问。SDS 报告了 Alnylam Pharmaceuticals、Amgen、AstraZeneca、Bristol-Myers Squibb、Gilead Sciences、GlaxoSmithKline、MyoKardia、Novartis、Theracos、Bayer 和 Cytokinetics 的资助和咨询费用（列出的所有费用已支付给 Brigham and Women's Hospital），资助来自Bellerophon Therapeutics、Celladon、Ionis Pharmaceuticals、Lonestar Heart、Mesoblast、Sanofi Pasteur 和 Eidos Therapeutics；Akros Pharma、Corvia Medical、Ironwood Pharma、默克、罗氏、武田制药、Quantum Genomics、AOBiome、Cardiac Dimensions、Tenaya Therapeutics 和 Daiichi Sankyo 的咨询费；